There continues to be a feared scenario of battlefield use of or domestic terrorist attacks with aerosolized microorganisms leading to mass infections. Given the added possibility of resistance to current treatments through genetic engineering or natural emergence, identifying new effective antibiotics is critical to counter such an attack. An effective therapeutic agent against a spectrum of inhaled pathogens is needed in the armamentarium of therapeutics to combat bioterror and biowarfare. It has been surprisingly discovered that triazole-containing macrolides and ketolides exhibit high activity on various organisms that pose a potential biowarfare and/or bioterror threat.
In one embodiment, compounds, compositions, methods, and medicaments are described herein for treating diseases arising from one or more bioterror and/or biowarfare agents. Illustrative agents include Bacillus anthracis (BA), Yersinia pestis (YP), Francisella tularensis (FT), Burkholderia mallei (BM), and B. pseudomallei (BP). In another embodiment, compounds, compositions, methods, and medicaments are described herein for treating diseases arising from one or more bioterror and/or biowarfare agents selected from B. anthracis, Y. pestis, F. tularensis, and B. mallei. It has been surprising discovered herein that the triazole-containing compounds described herein are highly active on F. tularensis. In another embodiment, the compounds, compositions, methods, and medicaments are useful as post-exposure prophylaxis agents, such as medical countermeasures, following an exposure or inhalation of a one or more bioterror and/or biowarfare agents. In another embodiment, the compounds, compositions, methods, and medicaments are useful in treating diseases caused by an exposure or inhalation of a one or more bioterror and/or biowarfare agents, including, but not limited to, pneumonia, plague, tularemia, meliodosis, and the like.
In one illustrative embodiment, compounds of Formula (I) are described herein
including pharmaceutically acceptable salts, hydrates, solvates, esters, and prodrugs thereof.
In one aspect, R10 is hydrogen or acyl. In another aspect, X is H; and Y is OR7; where R7 is a monosaccharide or disaccharide, alkyl, aryl, heteroaryl, acyl, or C(O)NR8R9, where R8 and R9 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; or X and Y are taken together with the attached carbon to form carbonyl.
In another aspect, V is C(O), C(═NR11), CH(NR12, R13), or N(R14)CH2, where N(R14) is attached to the C-10 carbon of the compounds of Formulae 1 and 2; wherein R11 is hydroxy or alkoxy, R12 and R13 are each independently selected from the group consisting of hydrogen, hydroxy, akyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; R14 is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, or carbamoyl.
In another aspect, W is H, F, Cl, Br, I, or OH.
In another aspect, A is CH2, C(O), C(O)O, C(O)NH, S(O)2, S(O)2NH, C(O)NHS(O)2. In another aspect, B is (CH2)n where n is an integer ranging from 0-10, or B is an unsaturated carbon chain of 2-10 carbons. In another aspect, C is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureido, or carbamoyl.
In another embodiment, compositions including a therapeutically effective amount of one or more compounds of formula (I), or the various subgenera thereof are described herein. The pharmaceutical compositions may include additional pharmaceutically acceptable carriers, diluents, and/or excipients.